DE2402391A1 - INDOLBENZA AZEPINE - Google Patents

Description

Certain "Octahydropyridoindolbenzazepines" are known from US Patents 3,373,168 and 3,457,271 According to these patents, compounds can be given by the formula

(D

in which R is a straight-chain or branched alkyl radical with 1 to 7 carbon atoms, are represented

According to ITJPAC rules of 1957, the same compounds are represented by the formula

4098 30/1106

(D

and designated as 1,2,3,4,4a, 8,9,14a-octahydropyrido- / 4 '»3 ¹ : 2,3_7indole / i, 7-ab_7 / i_7benzazepine. The representation and nomenclature of the IUPAC are used here.

The compounds of formula (1) have according to the USA patents 3,373,168 and 3,457,271 have antidepressant effects and are beneficial as antidepressants. These connections are according to these patents by reducing the corresponding hexahydro compounds either with Sodium produced in a mixture of tetrahydrofuran and liquid ammonia or with zinc in hydrochloric acid. The former Process is preferred by the patentees because higher yields can be achieved with it.

The compounds according to the invention have a different steric configuration of the hydrogen atoms on the 4a and 4a 14a positions as the compounds of the aforementioned USA patents. The proof of this is given by the fact that in the compounds according to the invention the hydrogen atoms the trans-configurations at the 4a and 14a positions and for the compounds of the named USA patents: have the cis configuration. The compounds according to the invention are obtained either directly or indirectly by reduction of 1,2,3,4,8,9-hexahydropyrido / 4'i3 '^^ Jindol / i ^ - aJl / benzaTiepinen made with borohydride / tetrahydrofuran complex. It has been shown that this leads to the trans configuration leads. In contrast to the connections of the

409830/1106

cited United States patents representing antidepressants are the compounds according to the invention in general central damping. ·.

The invention encompasses a class of compounds of the formula

R.
t

• (n) HX

in the

η = O or 1

χ = an anion of a pharmaceutically acceptable acid and

R = hydrogen, 3-chloro-2-butenyl, 2-bromoallyl, benzyl, benzyl ring-substituted with methyl, methoxy or chlorine, phenylethyl, 3-phenylpropyl, 3-phenylpropyl ring-substituted with chlorine, bromine or methoxy, furfuryl, 2-thenyl, Acetonyl, Phenacyl, C ₁ -C ₅ -AIkIyI, C ₅ -C ₅ -AllCenyl, Cz-Cj -alkynyl, cinnamyl, with chlorine, bromine or methoxy ring-substituted cinnamyl, 3-phenyl-2-propynyl, cyclopropyl, · C .-Cg-Cyeloalky-methyl, (methylcyclopropyl) methyl, (cis-2,3-dimethylcyclopropyl) methyl, Cg-Cg-Cycloalkenylmethyi, Cg-Cg-Cycloalkadienylmethyl, (2,3-Dimethylcycloprop-2-en-1-yl ) methyl, exo-7-norcarylmethyl, (cis-1,6-dimethyl-endo-3-norcaren-7-yl) methyl, (4-methylbicycloZ2 "2.27oct-1-yl) methyl, (4-methylbicyclo / 2.2 .27oct-2-en-1-yl) methyl, (bicyclo / 2.2 _O 27hept-2-yl) niGthyl, (bicyclo / 2.2.2 / hept-2-en-5-yl) methyl, 1-adamantylmethyl or 2-adamantylmethyl,!

40983 0 / 1.1 0 6

ι and the hydrogen atoms in the 4a and 14a positions in trans relationships with each other.

The invention includes pharmaceutical preparations which have a pharmaceutically acceptable carriers and a compound of formula I. ,

The invention is also directed to a method of producing an analgesic effect in warm-blooded animals by administration an analgesically effective amount of a compound of formula I directed.

Finally, the invention comprises the preparation of the compounds by a process which is characterized in that 3-substituted 1,2,3,4,8,9-hexahydropyriao / 4 ^l _f 3 'J2,37 indole / i, 7- ab7 / \ 7benzazepine is reduced with a borohydride / tetrahydrofuran complex and the compound of the formula I obtained is optionally further treated, for example by dealkylation, optionally with subsequent alkylation or acetylation / reduction, and thereby converted into another compound of the formula I. '

Synthesis of the compounds
All compounds are produced either directly or indirectly through reaction (1). The compounds obtained directly from reaction (1) can optionally be further treated, as shown in reactions (2) to (4), in order to prepare other compounds according to the invention.

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(D

II

ΒΗ, / ΤΉΡ

Yes

ClCOOR-

Ib

III

• he =

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III -R ^D C1

IV

^ / Catalyst

"C

R ^C Z

Ie

Ic

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Ie

Metal hydride

Id

In the above formulas, the members have the following meanings: j R ^a = benzyl, a benzyl radical substituted with methyl, methoxy or chlorine ringsul), phenylethyl, 3-phenylpropyl, a 3-phenylpropyl radical ring-substituted with chlorine, bromine or methoxy, furfuryl, 2-thenyl, Cj-C ^ -alkyl, cyclopropyl, C ^ -C ^ -cycloalkylmethyl, (methylcyclopropyl) -methyl, exo-7-norcarylmethyl, (4-methyrbicyclo / 2.2.27-oct-1-yl) methyl, (Bicyclo / 2.2.27hept-l-yl) methyl,

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1-adamantylmethyl or 2-adamantylmethyl; I.

- - a I

R has the same meaning as R or stands for

M 7

-C-R '

wherein R has the same meaning as R, excluding C ₂ -C alkynyl, 2-chloro-i-propenyl, 1-bromovinyl, cis-1,6-dimethyl-endo-3-norcaren-7-yl and phenylethinyl;

R = methyl, ethyl, benzyl, a benzyl radical which is ring-substituted with chlorine, methyl or methoxy, or a cyclopropylmethyl radical; i

i

R ^ = Cj-C, alkyl, vinyl, benzyl, p-methylhenzyl, p-methoxybenzyl or phenyl; ',

R ^c has the same meaning as R, excluding hydrogen, cyclopropyl and (cis-2,3-dimethylcyclopropyl) methyl;

!

R = 2-chloro-1-propenyl, 1-bromovinyl, phenyl, chlorophenyl, methylphenyl, methoxyphenyl, benzyl, phenylethyl, a phenylethyl radical ring-substituted with chlorine, bromine or methoxy, 2-furyl, 2-thienyl, hydrogen, C ^ - 0. -Alkyl, C ₂ -C ^ -AIkCHyI, C ₂ -C, -alkynyl, styryl, a styryl radical ring-substituted with chlorine, bromine or methoxy, phenylethinyl, C, -Cy-cycloalkyl, methylcyclopropyl, C ^ -C "-cycloalkenyl , Cc-C ₇ -cycloalkadienyl, 2,3-dimethylcycloprop-2-en-1-yl, exo-7-norcaryl, cis-1,6-dimethylendo-3-norcaren-7-yl, 4-methylbicyclo / 2.2. 2./oct-1 -yl, bicyclo / 2 = 2.27hept-2-yl, 4-methylhicyclo / 2.2.27oct-2-en-1-yl, bicyclo / 2.2.27hept-2-en-5-yl, 1-adamantyl or 2-adamantyl;

R has the same meaning as R exclusively hydrogen, acetonyl, phenacyl, cyclopropyl, cinnamyl, substituted Cinnamyl, 3-phenyl-3-propynyl and (cis-2,3-dimethylcyclopropyl) methyl;

U 09 b, 0/1106

-9- 2A02391

Q = -Cl, -Br, C ₁ -C ₄ -AlkOXy, R ^4- CO-,

0 0!

r5_J_q_ _{0 (s} j R ⁶ OC-Ot wherein R ^ R ^{4- comparable;}

divorced and a Cj-C ^ -AlkyIrest is with the proviso, that in cases where R ^ is hydrogen, R ^ is methyl;

ι R ⁶ = C ₁ -C ₄ '

_14th

8 8 Z = -Cl, -Br, -I or -OS (O) ₂ R, where R is a CH ^ group, phenyl or p-tolyl, and

R ⁰ Z can also be R ⁹ OS (O) ₂ OR ⁹ , where R ^{9 is} a Cj-C ^ alkyl-

rest is. !

The compound of the formula I in which R is a (cis-2,3-dimethylcyclopropyl) methyl radical is, can by catalytic hydrogenation of the compound of formula I in which R is a (2,3-Dimethylcycloprop-2-en-1-yl) methyl radical, at room temperature getting produced. A suitable catalyst is, for example, 5% palladium-carbon.

Raw materials

The 1,2,3,4,8,9-hexahydropyrido / 4 ·, 3 ': 2,37indole / i, 7-ab7 / \ 7-benzazepine of the formula II can, for example, according to the USA patents 3,373,168 mentioned above and 3,457,271 processes described, namely by N-hydrogenation of iminodibenzyl, reduction of the product to N-aminoiminodibenzyl,

Condensation with an appropriately substituted 4-piperidinone and cyclization with an acid. The methyl- and ethyl-substituted hexahydropyridoindolbenzazepines are known compounds. Several other ^ -substituted hexahydropyridoindo! Benzazepines are described in US Pat. No. J> 764,684. The compounds of the formula II in which R ^{2 is} « ₇ ,

-C-R 'can of course by customary acylation

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the corresponding compound in which R is hydrogen, using a suitable acylating agent how to make acyl chloride. These compounds can also be obtained by condensation of N-aminoiminodibenzyl made with the appropriate i-acyl-4-piperidone will.

Reaction (1)

The reduction of the hexahydro precursors to the octahydro compounds is best carried out with a 4- to 5-fold excess of the borohydride / tetrahydrofuran complex at low temperature down to ⁰ ° C. or at high temperature up to the reflux temperature of tetrahydrofuran The hydride / tetrahydrofuran complex can be increased further by dilution with a higher-boiling ether, for example diglyme, whereby it is possible to carry out the reaction at a higher temperature, which is usually not above 100 to 110 C. The reaction mixture is then at approximately 4-10 molar hydrochloric acid acidified, ^{heated to 100 °} C., left to cool and neutralized with caustic alkali The product can be isolated in any suitable manner, for example by extraction, evaporation with subsequent extraction and conversion into an addition salt.

The particularly outstanding feature of the compounds of the formula Ia, i.e. those compounds of the formula I which directly by reducing the hexahydro precursors with BH-z / THF complex can be produced is their central depressant effect (more specifically their effect as a sedative Tranquilizers), which is completely unexpected in view of the disclosures in U.S. Patents 3,373,168 and 3,457,271 is. It is believed that this effect is related to the steric configuration of the compounds according to the invention is related, however, it is not intended to be bound by this theory. Still lie the proposed Structure of the compounds according to the invention

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are based on the following considerations and points of view:

a) It was found by mass spectroscopy that by reducing a hexahydro compound (3) with borohydride in tetrahydrofuran the molecular weight is increased by 2. This means that two hydrogen atoms are attached have been.

b) The ultraviolet spectrum shows that from the rings -C and E and the nitrogen atom in the 14-position Diphenylamine chromophore unchanged after reduction is. This means that the aromatic rings C and E have been retained.

c) A reducing cleavage of the Cg-Cg bond, which includes the benzyl carbons, separates both according to the UV spectrum as well as the nuclear magnetic resonance spectrum. ;

d) The only remaining option is to saturate the C. -C ... double bond. ·

e) The nuclear magnetic resonance spectrum of the known octahydro compounds shows that they have the cis configuration. '.

The formation of octahydroindolbenzazepines, in which rings B and C represent an indoline component, according to the The method according to the invention is not only new but also completely surprising, especially in view of the Results of a recent study on the conversion of indoles with diborane by Monti and co-workers (Tetrahedron 27 (1971) 3331).

In this description and in the claims the compounds according to the invention are referred to as trans compounds referred to to distinguish them from the compounds that have the configuration used in the United States patents 3,373,168 and 3,457,271.

U 0 9 H, U / 1 1 0 6

However, this designation is used on the assumption that that if it is finally demonstrated that either this assignment of the isomer is incorrect or one completely different isomerism is present, the term "trans" used here nevertheless denotes the compounds which the Configuration of the connections specifically described here. The steric configuration of the compounds according to the invention can thus be characterized as having the configuration identical to the configuration in the reduction of the C, -C .., double bond with the Borohydride / tetrahydrofuran complex results.

/
Reaction series 2 ;

The compounds of the formula I in which R is a hydrogen atom (formula Ie) cannot be carried out directly by reduction the corresponding hexahydro compound with the BH, / THF complex getting produced. The hexahydro compound is in an attempt to reduce even with BH ^ / THF in Diglyme isolated unchanged. Accordingly, the compounds of the formula Ie from compounds of the formula Ib with the help of the reaction series (2).

In reaction series (2), the compound of the formula Ib is first reacted with a chloroformate ClCOOR. This reaction may be at a temperature in the range of 20 to 110 C, preferably at 90 ° to 11O ⁰ C, are carried out in an inert organic solvent such as benzene, toluene or dioxane. The quaternary ammonium salt III initially formed by the reaction with the chloroformate is not isolated and the reaction proceeds to the compound of the formula IV. The latter connection can, but need not, be isolated. The hydrolysis of the compound of the formula IV to form the compound Ie can be carried out in a C 1 -C 4 alkanol containing 0 to 10/6 water and a hydroxide of potassium, sodium, lithium or calcium at a temperature in the range from 65 to 14 -0 ⁰ C can be carried out. It can also be in a watery one

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Mineral acid (eg acetic acid or hydrochloric acid) 11O ⁰ C be carried out at a temperature in the range of 20 ms. The hydrogenolysis, which is applicable when R is a benzyl radical or substituted benzyl radical, can be carried out at a hydrogen pressure of 1 to 3 atm. and carried out at a temperature in the range from 30 to 60 ⁰ C using a platinum, palladium or Raney nickel catalyst »

Reaction (3)

By reducing with the BEz / THF complex in the reaction (1) becomes not just the indole double bond of the hexahydro precursor, but also any carbonyl group and / or olefinic or acetylenic multiple bond of the radical R reduced. As a result, connections of the Formula I containing reducible radicals R by alkylation or acylation / reduction of the octahydro compounds, in which R is hydrogen (formula Ie), according to reaction (3) and reaction series (4). Of course, compounds that are.non-reducible R contains radicals, with the exception of compounds in which R is hydrogen or cyclopropyl, too can be produced by these methods. i

The reaction (3) is a common alkylation reaction. The reagent R ^C Z is an organic halide (Z = Cl, Br or I), sulfate (R ⁰ Z = R ⁹ OS (O) ₉ OR ⁹ ) or sulfonate (Z = -OS (O) pR) · The reaction is carried out in a polar organic solvent, for example in dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, acetone, ethyl ethyl ketone, methanol or ethanol, in the presence of an alkali or alkaline earth carbonate or bicarbonate or a tertiary amine, for example pyridine or triethylamine. Reaction temperatures ranging from 0 ° to 100 C may be employed, with a range is preferably from 20 to 40 ⁰ C.

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Reaction series (4)

Reaction series (4) is a common acylation / reduction. The acylating agent 0 is an acid halo

QCR ⁴ "

nid (Q = Cl, Br), ester (Q = C ₁ -C. -alkoxy), anhydride O ' ⁴ O

(Q = R-C-O) or mixed anhydride (Q = R-C-O-)

including mixed anhydrides with an ester of

6 "\
"Carbonic acid (Q = R 0-C-0). The acylation is in an organic solvent such as benzene, chloroform or dichloromethane at a temperature of 0 °" 80 ° C, preferably from 0 ° "to 40 ⁰ C. When using an acid halide as acylating agent, an inorganic or tertiary amine base is present for the reaction with the acid released (2-methoxyethoxy) aluminum hydride in a solvent such as benzene or! toluene at a temperature in the range of 30 to 100 ⁰ C, preferably from 30 to 65 ° C. glyme and diglyme are common designations of ethylene glycol dimethyl ether or Diäthylenglykoldiäthylather.

As examples of representative, pharmaceutically acceptable acids which can be used for the preparation of the acid addition salts according to the invention, there may be mentioned: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, citric acid, 4.4 ^r - Methylene-bis (3-hydroxy-2-naphthoic acid), succinic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid,

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2A02391

Aspartic acid, stearic acid, palmitic acid, itaconic acid, Glycolic acid, p-aminobenzoic acid, glutamic acid and toluenesulfonic acid.

Stereoisomers

All compounds of the formula I have at least two asymmetric centers which result from the reduction of the £ ^ ^a * ^4a system to the linked trans system. The invention includes the racemates and the individual enantiomers. Furthermore, when the 3-substituent includes a moiety which can exist in stereoisomeric forms, the resulting diastereoisomers also fall within the scope of the invention.

Examples

The preparation of the compounds according to the invention is described in the following examples. In these examples All parts, proportions and percentages relate to the weight, unless stated otherwise.

Example 1 j

trans-1,2,3,4,4a, 8,9,14a-octahydro-3-methylpyrido / 4 ', 3': 2,57indole / i.7-ab7 / V7benzazepine ^;

A solution of 4.76 g of 1,2,3,4,8,9-hexahydro-3-methylpyrido / 4 ^l , 3I: 2,27 indole / 1,7-ab7 / l7benzazepine (the one described in the US patent 3,457,271, column 4, lines 27-54) in 50 ml of tetrahydrofuran was added dropwise with stirring to a 1N solution of borohydride in tetrahydrofuran (42 ml) under nitrogen. After the addition was complete, the mixture was refluxed under nitrogen for 5 hours, then cooled in ice and deactivated with 20 ml of 6N hydrochloric acid. The mixture was distilled and the removed liquid was replaced from time to time by the addition of dioxane. The mixture was heated again for 1 hour at 91 ⁰ C on the reflux condenser with additional 6N hydrochloric acid, then ^{cooled to 7O 0} C, made basic with sodium hydroxide and under mixed

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2A02391

- I D -

evaporated under reduced pressure. The semisolid residue was treated with water and chloroform and the chloroform layer was worked up further, 1.50 g of a solid product with a melting point of 128 to 131 ^° C. being obtained. The mother liquor gave an additional amount of product with a melting point of 129 »5 to 130.5 ° C. The melting point was increased to 132 to 134 ° C by crystallization from ether.

UV spectrum: λ ^ 3 ^υη 279.5 mu (log £ 4.13).

By reducing 1,2,3,4,8,9-hexahydro-3-methylpyrido- / 4 ', 3': 2,37indole / i _f 7-ab7 / i7benzazepine with sodium in liquid ammonia, the well-known cis-octahydro compound became 120-122 ⁰ C obtained from the melting point.

mju (log £ 4.08).

The trans-1,2,3,4,4a, 8,9,14a-octahydro-3-methylpyrido-Z4 ', 3': 2,57indole / 1 ^ -abJ / T / ^ enzazepine according to the invention can also by the following method, in which a reducing Cleavage of the 3-methoxymethylhexahydro compound is carried out in the manner described below, getting produced:

A. A mixture of 2.74 g (0.01 mole) 1,2,3,4,8,9-hexahydro pyrido / 4 ', 3': 2,3_7indole / i, 7-ab7 / i_7benzazepine in the manner described in Section -A of Example 2, and 75 ml of dry benzene was heated to boiling until Resolution occurred. After adding 10.5 ml (0.075 mol) Triethylamine to the warm solution were 2.0 ml (0.026 mol) Chloromethyl methyl ether was added dropwise. The resulting mixture was refluxed for 15 minutes, to room temperature cooled and filtered. The piltrate after evaporation gave 3.05 g of a yellow oil which according to the infrared spectrum contained no free = NH groups.

B. The product from the previous stage (3.0 g, 0.01 mol)

in 50 ml of freshly purified tetrahydrofuran was added dropwise with stirring and under nitrogen to 75 ml of one

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1 molar solution of borohydride given in tetrahydrofuran. The resulting mixture was refluxed under nitrogen for 26 hours, then cooled in ice and carefully decomposed with 50 ml of 5.5N hydrochloric acid. About 30 ml of the liquid was distilled off. To dissolve the precipitate formed again, 50 ml of glacial acetic acid were added. The solution was heated for a further hour at reflux, cooled to 55 to 60 ⁰ C and basified with 50 $ ethyl caustic. The product was isolated by extraction with ether, evaporation of the solvent and column chromatography in a benzene solution on basic aluminum oxide I. The pure product had a melting point of 136-138 ° C. and was identical to the product which had been prepared by the first process described in this example. ^:

Example 2

trans-3- (Cyclopropy! methyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ' , 3 ': 2,3_7indole / 1,7-ab_7 / "1_ / benzazepine

A. A mixture of 24.6 g of N-aminoiminodibenzyl (5-amino-10,11-dihydro-5H-dibenz / b, f7azepine) and 14.8 g of 4-piperidone hydrochloride in 250 ml of ethanol was heated on the steam bath for 15 minutes and chilled. Then a solution of 20 g of concentrated sulfuric acid in 250 ml of ethanol was added. The mixture obtained was heated on the steam bath for a further 40 minutes. The resulting solution was cooled, made basic with ammonia and diluted with 1 liter of water. The crude, semi-solid material which separated out was taken up in ether and the aqueous mother liquor extracted with additional portions of ether. The combined ether extracts were concentrated to 500 ml and treated with 50 ml of 5N hydrochloric acid under nitrogen with vigorous stirring. The precipitate formed was filtered off, washed with ether and 1N-hydrochloric acid and then under reduced pressure at 100 ⁰ C dried to give 1,2,3,4,8,9-hexahydro-pyrido / 4 ^f, 3 ': 2,3_ / indole / i, 7-ab // i_7benzazepinhydro-

09830/1106

Chloride with a melting point of 309 ° C. was obtained as a salt which was only very slightly soluble in water. By dissolving this salt in aqueous acetic acid, basifying with ammonia, filtering off the crude product and recrystallization from benzene, the free 1,2,3,4,8,9-hexahydropyrido / 4 ^I , 3 ^f : 2,3_7indole / ~ 1, 7-ab.7 / i. / Benzazepine regressed.

B. To a solution of 16.4 g of 1,2,3,4,8,9-Hexahydropyrido- / 4 ^l, 3 ': 2,3_7indol / ~ 1, 7-AB7 / V7benzazepin i _n 500 ml of dichloromethane were added 7 , Added 3 g of cyclopropanecarbonyl chloride, whereupon 10 ml of triethylamine were added dropwise. ^v A slightly exothermic reaction took place, after which the mixture was further stirred at room temperature overnight. The mixture was then washed with 1N hydrochloric acid and water and dried over anhydrous sodium carbonate. Crude 3- by evaporation to dryness (cyclopropylcarbonyl) -1,2,3,4,8,9-hexahydropyrido / 4 ', 3': 2,3_7indol / i, 7-AB7 / i_ / ^z Bess azepine (Formula 4 , in which R ¹ stands for cyclopropyl) obtained as a glassy product. By recrystallization from ethanol, the pure product "was obtained, mp 154- to 156 ⁰ C.

A solution of 8.6 g of this compound in 120 ml of tetrahydrofuran was added dropwise to a suspension of 2.3 g of lithium alaininium hydride in 180 ml of tetrahydrofuran. After the addition had taken place, the mixture was first refluxed for 4 hours, then at overnight Stirred at room temperature and finally decomposed in the usual way. The inorganic salts were filtered off and the filtrate was dried over anhydrous sodium carbonate and evaporated under reduced pressure. The residue was dissolved in a 1: 1 mixture of ethyl acetate and benzene and applied to a 14 x 2.2 cm column of basic Activity I aluminum oxide is chromatographed. The eluate was evaporated to dryness. That remaining as residue Oil was dissolved in absolute alcohol, saturated with ethanolic hydrochloric acid and again brought to dryness.

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steams. After crystallization of the residue from acetone, trans-3- (cyclopropylmethyl) -1 pyrido / A ¹ , 3 ': 2.5 / indole / i, T-ab / Zi /

(Formula 3, where R = cyclopropylmethyl) from the melting point 267 ° C obtained. .

C. A solution of 9.25 g of the free base of the hexahydro compound prepared as described above in 75 ml of tetrahydrofuran was mixed with 100 ml of a! "" - molar solution of borohydride in tetrahydrofuran after in the procedure described in Example 1 reduced. The title compound weighed 4.43 g and had a melting point of 152.5 to 155 ° C. UV spectrum:

281 mu (log ε 4.10). The hydrochloride had a melting point of 273 to 276 ^° C. j

The cis- Product obtained which formed a hydrochloride with a melting point of 241 to 243 ^° C. UV spectrum: λ ^ ^0Η 285 mu (log £ 4.10).

It was found by thin layer chromatography using a mixture of chloroform, butanol and 28% aqueous ammonia in a volume ratio of 95: 10: 5 as a solvent that the above two octahydro compounds had different R _f values.

Example 3

trans-3- (Cyclopropylmethyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3',: 2,3_ / indole / i, 7-ab_7 / i_7benzazepine (by a step Reduction)

A solution of 100 g of 3- (cyclopropylcarbonyl) -1,2,3,4,6,9-hexahydropyrido / 4 ', 3 ¹ : 2,3_7indole / i, 7-ab7 / i7benzazepine in 50 ml of tetrahydrofuran was obtained within 30 Added minutes to about 946 ml of a 1 molar solution of borohydride in tetrahydrofuran. The resulting solution was 72 hours

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left to stand, whereupon a solution of 50 ml of concentrated hydrochloric acid in 100 ml of water was added. The mixture was distilled when the pot temperature reached 100.degree. The material remaining as residue was cooled and diluted with 200 ml v / water and 75 ml 50% sodium hydroxide. The product was extracted with methylene chloride and, after treatment of the residue remaining after the methylene chloride had been distilled off, was isolated as a crystalline material. Yield 60.3 g, melting point 146-151 ⁰ C. After recrystallization from methanol-chloroform in a volume ratio of 9: 1 of the increased melting point 153-155 ⁰ C.

A sample of this product was converted to the mesylate (methanesulfonate) of melting point 227-232 ⁰ C.

Example 4

trans-3-ethyl-1,2,3,4,4a, 8,9,14a-oc tahydropyrido / 4 ', 3': 2, 3j indole / ϊ, 7-ab_7 / \ 7benzazepine

To a mixture of 9.0 g of N-nitrosoiminodibenzyl, 12.4 g 1-acetyl-4-piperidone and 13 »0 g zinc dust ■ in 75 ml absolute Ethanol was added dropwise to 24 ml of glacial acetic acid with constant stirring, with occasional cooling, to keep the reaction temperature at 20-25 ° C. To The unchanged zinc was filtered off in 6 stands and the mother liquor was evaporated to almost dryness. The residue was extracted with benzene, the extract was washed with saturated sodium chloride solution and dried over magnesium sulfate dried and the solvent evaporated. The yellowish-brown residue was dissolved in 50 ml of ethanol, treated with a solution of 8 ml of concentrated sulfuric acid in 50 ml of ethanol and put on the steam bath for about 10 minutes heated. The mixture was poured into cold water, a gummy material separating from which the aqueous layer was decanted. After dissolving the gummy material in ethyl acetate, the solution was with

£ 09830/1106

washed saturated sodium chloride solution and ü "dried over sodium sulfate. After evaporation of the solvent. 'by means of an off-white solid was obtained which was crystallized from acetone to give 3-acetyl-1,2,3,4,8, 9- hexahydropyrido 4 ', 3' / *: was / i 7-AB7 / receive 2,3_7indol, i7benzazepin Peststoff as a white of melting point 193-196 ⁰ C.

This 3-acetyl compound was reduced in the manner described in Example 3 with borohydride in tetrahydrofuran. The desired compound was obtained in a yield of 36 $ isolated as the hydrochloride of melting point 258 to 26O ⁰ C (dec.). UV spectrum: X ^ ° ^H 276 mi (log £ 4.11). The above compound can also be prepared by reducing the 3-acetyl compound under more severe conditions as follows:

A warm solution of 11.53 g (0.0365 mol) of the 3-acetyl compound in 300 ml of diglyme is added dropwise rapidly to a mixture of 250 ml of diglyme and 150 ml of 1 molar borohydride in tetrahydrofuran. The mixture is then stirred for 20 hours under nitrogen at 100 ⁰ C, the mixture cooled to 2O ⁰ C, decomposed with 75 ml of 10N hydrochloric acid and heated for 1 hour at 9O ⁰ C under a reflux condenser. It is cooled to 6O ⁰ C, basified with 100 ml of 50 $ strength caustic alkali, concentrated under reduced pressure and extracted with chloroform. The 3-ethyl product is obtained from the chloroform extract in a yield of 67%.

Example 5

trans-1,2,3,4,4a, 8,9,14a-octahydro-3-isobutylpyrido / 4 ', 3 ': 2,3_ / indole / i, 7-ab_7 / i_ / benzazepine

, 3 ': 2,3_7indole-

/ Ί, 7-ab_7 / i_7benzazepine ^{with a} melting point of 122 to 124 ° C was obtained by reacting 1,2,3,4,8,9-hexahydropyridoZ4 ', 3': 2,3_7-indole / i, 7-ab // i_7benzazepine made with isobutyryl chloride. This amide was made with borohydride tetrahydrofuran

409830/1 1 06

in diglyme in the above as an alternative method for reducing the 3-acetyl compound to the 3-ethyl compound of Example 4 described manner reduced.

The desired compound was isolated as the hydrochloride with a melting point of 286 to 289 ° C. (decomp.).

Example 6

trans-3-benzyl-1,2,3,4,4a, 8,9, Ha-octahydropyrido / V, 3 ': , 7-ab_7 / i.7benzazepine

By condensing N-nitrosoiminodibenzyl with 1-benzyl-4-piperidone under the conditions mentioned in Example 4 for the condensation with "1-acetyl-4-piperidinone, 3-benzyl-1, 2,3,4,8,9- hexahydropyrido / 4 ^l , 3 ': 2,3_ / indole- / Ϊ _t 7-ab // \ / benzazepine (hydrochloride with a melting point of 200 ° C.) by reducing the free base with a borohydride-tetrahydrofuran complex in diglyme under the conditions The alternative method for reducing the 3-acetyl compound described in Example 4 gave the desired compound in a yield of 84 / =. The product was isolated as the hydrochloride with a melting point of 210 to 212 ° C. (decomposition). The free base was obtained by treating the Hydrochloride obtained in methanol solution with anhydrous ammonia The free base had a melting point
(log Ε 4.13)

Melting point from 146 to 148 ⁰ C. UV spectrum: λ !? ^Η $ ^0Η 279mu

Example 7

trans-1,2,3,4,4a, 8,9,14a-octahydro-3- (exo-7-norcarylmethyl) pyrido / 4 ^! , 3 ': 2,37inäol / i, 7-ab // i7benzazepine

A solution of 7.05 g (0.0178 mol) 1,2,3,4,8,9-hexahydro-3-Z "(exo-7-norcaryl) carbonyl_7pyrido / 4 ^l , 3 ': 2,3_7indole / i, 7-ab_7 - / \ 7benzazepine, which is derived from 1,2,3,4,8,9-hexahydropyrido / 4 ^f , 3 ': 2, l7indole / i, 7-ab_7 / i_7benzazepine and (exo-7-norcaryl ) carbonyl chloride had been prepared in 100 ml diglyme was added dropwise under nitrogen with stirring to a mixture of 100 ml 1 molar borohydride in tetrahydrofuran

409830/1106

and given 400 ml diglyme. The mixture was kept for 23 hours at 110 ⁰ C and cooled to about 2O ⁰ C. After addition

75 ml 1ON HCl, the mixture was heated for 1 hour at reflux at 10O ⁰ C, cooled to about 6O ⁰ C and basified with 100 ml of 50 $ NaOH. The product was isolated and purified by repeated extraction and recrystallization. It had a melting point of 186 to 187 ^° C

Other representative compounds of formula (1) prepared by the methods described above are mentioned below.

1) trans-3-Cyclohexylmethyl-1, 2,3,4,4a, 8,9,14a-octahydropyrido / 4 ¹ , 3 ' : 2., 3jinäol £] ^ -abZ / iTbenzazepine hydrochloride, melting point 180 ⁰ C (dec .) ■

2) trans-3-Cyclopentylmethyl-1,2,3> 4,4a, 8,9,14a-octyhydropyrido / 4 ¹ , 3 ': 2,37indole / ~ 1,7-ab7A7benzazepine hydrochloride, melting point 263 ° C (dec. )

3) trans -3-Cyclopropyl-i, 2,3,4,4a, 8,9, Ha-octyhydropyrido-Z4 ', 3': 2,37iodol / 1,7-ab7 / 17 ^ enzazepine hydrochloride

4) trans -3- (1-adamantylmethyl) -1, 2,3,4 ^, 8,9,14a-octahydropyrido / 4 ' , 3 ': 2.37 indole / i, 7-ab7 / l / benzazepine hydrochloride

5) trans -3- (2-adamantylmethyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3': 2 _f 37in ^ olZi, 7-ab7 / 17'ben ^e.g. azepine hydrochloride

6) trans-3-Z * (cis-2,3-dimethylcyclopropyl) methyl7-

112,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3': 2,37 indole- / Ϊ, 7-ab7Zl7T3enzazepine hydrochloride

7) trans-1,2,3,4,4a, 8,9,14a-octahydro-3 - / "(4-methylbicyclo- / 2.2.? 7oct-1-yl) methyl7pyrido / 4 ^!, 3 ': 2 , 37indole / 1,7-ab7 - / "l / benzazepine hydrochloride

8) trans-1,2,3,4,4a, 8,9,14a-octahydro-3-: £ (1-niethylcyclopropyl) methyl7pyrido / 4 ', 3 ".2

409830/1106

benzazepine hydrochloride

9) 1; rans-3 - / "(bicyclo / 2.2.i7hept-2-yl) methyl7-1,2,3,4,4a, 8, 9,14a-octahydropyrido / V, 3 ': 2,37 indole / i, 7-abJf \ J- benzazepine hydrochloride

10) trans -3-furfuryl-1,2,3,4,4a, 8,9, Ha-octahydropyrido- / V, 3 'ί2, J> Jxnaol. [\ , 7-ab7Yl7benzazepine hydrochloride

11) trans-3- (4-chlorobenzyl) -1,2,3,4,4a, 8,9,14a--octahydro-pyrido / V, 3 ^1: 2,37indol / i, 7-AB7 / ^e l7fr nzazepinhydrochlorid

12) trans -3 (2-methoxybenzyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / V, 3 ': 2,37 indole / 1,7-ab7 / 17 ^ en ^z azepine hydrochloride

13) trans -3 / 3- (2-chlorophenyl) propyl7-1,2,3,4,4a, 8,9,14aoctahydropyrido / 4 ', 3': 2,37indole / i ₎ 7-ab7 / i7t ^| en ^zaz epine hydrochloride

14) trans-3- / 3- (4-bromophenyl) propyl7-1,2,3,4,4a, 8,9,14aoctahydropyrido / 4 ', 3': 2,37indole / i, 7-aby / i7benzazepine hydrochloride '

propyl / pyrido / 4 ', 3 *: 2.37 indole / l, 7-ab / ^ J7benzazepine hydrochloride

16) trans -3-cycloheptylmethyl-1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3 ': 2,37 indole / * 1,7-ab7 / i7benzazepine hydrochloride

17) trans-1,2,3,4,4a, 8,9, Ha-octahydro-3-phenethylpyrido-ZV, 3 ': 2,37indole / i, 7-ab7 / i7l'enzazepine, melting point 270 ⁰ C ( Decomp.)

18) trans-1,2,3,4,4a, 8,9,14a-octahydro-3- (3-phenylpropyl) -pyrido / 4 ', 3': 2, ^ indole / i, 7-ab7 / i7benzazepine

19) trans-i, 2,3,4,4a, 8,9,14a-octahydro-3- (2-thenyl) pyrido-Z "4 ^!, 3 ': 2, 37indole / i, 7 ~ ab7 / ~ i7benzazepine

20) trans-1,2,3,4,4a, 8,9,14a-octahydro-3-pentylpyrido-A ', 3 ^! : 2,37indole / i, 7-ab7 / i7benzazepine

21) trans-1,2,3,4,4a, 8,9, Ha-octahydro-3-neopentylpyrido-Z4 ', 3 ': 2.37 indole / i, 7-ab7 / i7benzazepine

22) trans-1,2,3,4,4a, 8,9,14a-octahydro-3 - / "(2-methylcyclopropyi) _m ethyl / pyrido / 4 ', 3': 2,37indole / i, 7- _a b7 / "t7-benzazepine

40983Ü / 1 106

Example 8 '

(+) - trans-1,2,3,4,4a, 8,9, Ha-octahydropyrido / 4 ¹ , 3 ': 2,37 ~ indole / i, 7-ab7 / * 1_7benzazepine and its salts ^;

A solution of 4.2 ml of ethyl chloroformate in 35 ml of dry benzene became a solution of 3.9 g of (+) - trans-3- (cyclopropylmethyl) -1,2,3,4,4a, 8,9,14a -oc tahydropyrido / 4 ', 3': 2.37 indole / i, 7-ab7 / i7t> enzazepine given in 100 ml of dry benzene. The solution was heated to reflux temperature with stirring, a white precipitate forming. The reflux condenser was heated for a further 3.5 hours, after which the reaction mass was cooled and filtered. This collected 0.43 grams of solids. The filtrate was evaporated to dryness leaving a heavy yellow oil. This oil was dissolved in 100 ml of n-butanol. 10 g of KOH in tablets were added to the solution, whereupon the mixture was refluxed with stirring for 1 hour. The mass was then cooled and concentrated. The residue was partitioned between toluene and water. The toluene solution was then extracted with water until the extracts were neutral. The toluene solution was then extracted four times with 100 ml of aqueous 2N tartaric acid each time. The combined extracts were washed once with ether and then made basic with sodium hydroxide. The oily product was extracted twice into methylene chloride. The combined extracts were washed and dried over potassium carbonate. The solution was then filtered and evaporated to give a pale yellow oil which crystallized under pentane. Recrystallization from about 50 ml of hexane / benzene gave 1.68 g of (+) - trans-1,2,3,4,4a, 8,9,14a-octahydropyridoZ4 ', 3': 2,37indole / ϊ, 7- AB7 / \ 7 "benzazepine obtained in the form of yellow crystals of melting point 148.5 to 149.5 ⁰ C.

The mother liquor from the crystallization was evaporated to dryness. The residue was dissolved in ethanol and then treated with excess tartaric acid in ethanol.

4-09830 / 1106

Here, a yellow oil, from the tartrate of the desired compound of melting point 255-256 ⁰ C (dec ") was obtained as a white solid by heating at reflux in ethanol was formed.

The corresponding hydrochloride is produced in the same way by treating the mother liquor with ethanolic HCl obtained from melting point> 325 ° C.

Example 9

(+) - trans-1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3': 2,37-indole / i , 7-ab // i_7benzazepine

A suspension of 70 g of {+ _ ) -trans -3- (cyclopropylmethyl) -1,2,3,4,4a, 8,9,14a-oc tahydropyrido / 4 ', 3': 2, 3j ± nolß , 7 -ab7- / I7benzazepine in 500 ml of dry benzene was heated with a solution of 83 ml of ethyl chloroformate in 250 ml of benzene. The solution was then refluxed for 3.5 hours. The solids were filtered off (6.2 g) and the filtrate was evaporated to give an oil which began to solidify. By recrystallization from 600 ml of ethanol 5.3 »4 g of ethyl - (+) - trans-1,2,3,4, 4a, 8,9,14a-oc tahydropyrido / 4 ', 3': 2,37indole / l, 7-ab // i7-benzazepine-3-carboxylate was obtained as a white solid with a melting point of 146.5-146.9 ° C.

The recrystallized ester was added to a solution of 60 g of KOH in 500 ml of n-butanol. The solution was Heated for 2 hours on the reflux condenser. The reaction mass was then cooled and reduced to about half volume and then treated with toluene and water. The toluene layer was washed with water until the extracts were neutral. She was then six times with 250 ml 1 molar tartaric acid extracted in water. The combined extracts were then extracted once with ether, cooled and with 50% sodium hydroxide to a ρττ value of more set as 11. A precipitate was formed here.

409830/1 106

2A02391

The material was then extracted _{several times with CH 2} Cl _2. The extracts were combined, washed with water, _{dried over K 2} CO ₅ , filtered and evaporated to give an oil. This oil was taken up in approximately 75 ml of benzene. The mixture was diluted with about 300 ml of hexane. The solution was kept at 4 ° C. overnight, during which time crystallization took place. The crystals were filtered off, washed with benzene / hexane and dried. In this case were obtained 148-149 ⁰ C g of the desired product in the form of yellow crystals of melting point 26.9.

Example 10

(+) - trans-3- (3-chloro-2-butenyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ¹ , 3 ': 2,3_ / indole / i, 7-ab_7 / i / benzazepine

A suspension of 2.76 g (+) - trans-1,2,3 _f A, 4a, 8.9, Ha-octahydropyrido / 4 ¹ , 3 ': 2,3_ / indole / 1,7-ab7 / i_7benzazepine in 20 ml of dimethylformamide (DMF) containing 2.3 ml of triethylamine was treated with 1.25 g of 1,3-dichloro-2-butene. The dissolution took place immediately. The solution was stirred for 4 hours at room temperature, during which time a certain amount of a white precipitate formed. The reaction mixture was poured into 150 ml of cold water, a gummy solid separating which was washed by decantation with cold water. By recrystallization from ethanol, were obtained 2.93 g of the desired compound of melting point 130-132 ⁰ C.

Example 11

(+) - trans-1,2,3,4,4a, 8,9,14a-octahydro-5- (2-propynyl) pyridoA ', 3': 2,37indole / i, 7-ab7 / i7benzazepine

2.38 g propargyl bromide were added to a solution of 5.52 g (+) - trans-1,2,3,4,4a, 8,9,14a-octahydropyrido / 4'f3 ': 2,37-indole / i , 7-ab7 / i7benzazepine and added 3 ml of triethylamine in 90 ml of dimethylformamide. The mixture was 4.5 hours at Room temperature stirred. A certain amount of precipitate formed here. The reaction mixture was in 300 ml

409830/1106

poured cold water. A plague was precipitated here, which was filtered off and washed with cold water. By recrystallization from 300 ml of ethanol 4.05 g of the desired compound were obtained in the form of pale yellow needles with a melting point of 160-161.5 ° C. One The analytical sample was recrystallized again from ethanol, almost colorless needles with a melting point of 162-163 ° C. being obtained became.

Example 12

(+) - trans-3-acetonyl-1,2,3,4,4a, 8,9,14a-octahydropyrido- / 4 ', 3' : 2,3_ / indole / i, 7-ab // i_ / benzazepine

5 ml of triethylamine were added to a solution of 2.8 g of (+) - trans-1,2,3,4,4a, 8,9, Ha-octahydropyrido / 4 ¹ , 3 ': 2,3 / -indole / ΐ , 7-ab_7 / 1_7benzazepine in 50 ml of dimethylformamide, whereupon 1 g of chloroacetone in 5 ml of DMi ^{1 was} added. The mixture was stirred at room temperature for 3.5 hours, poured into 100 ml of water and then extracted with ether. The ether was washed with water, with Na ₂ SO. dried, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in benzene and then chromatographed through basic alumina using benzene as eluent to give 1.5 g of the desired compound of melting point 128.5 ⁰ C (dec.) Were obtained. Another name for the desired compound is (+) - trans-1- (i, 2,3,4,4a, 8,9, Ha-octahydropyrido / 4 ', 3': 2,3_ / indole / i, 7 -ab_7 / \ 7benzazepin-3-yl) -2-propanone.

Example 13

(+) - trans -3-allyl-1,2,3,4,4a, 8,9,14a-octahydropyrido- / 4 ¹ , 3 ': 2,37 indole / i, 7-ab // i_ / benzazepine hydrochloride

4.2 ml of triethylamine were converted into 2.8 g of (+) - trans-1,2,3,4,4a, 8,9, Ha-octahydropyrido / 4 ', 3': 2,3_ / indole / i, 7-ab7 / i7benzs' /. E ~ pin in 50 ml of DMF, whereupon 1.6 g of allyl bromide in 5 ml of DMF were slowly added «The mixture was

409Ö30 / 1106

3.5 hours "stirred at room temperature, then poured into 125 ml of water and extracted with ether. The ether was washed once with water, _{dried with Na 2} SO. And evaporated to dryness under reduced pressure. The residue was dissolved in anhydrous ether dissolved and the desired compound precipitated by adding hydrogen chloride.After recrystallization from acetone, the product had a melting point of 231-232.5 ° C. (decomp.).

Example 14

(+) -trans-3-Z "(3-Cyclohexen-1 -yl) methyl7-1, 2,3, 4, 4a, 8,9, Haoctahydropyrido / 4 ', 3 ^M : 2,3. / indole / i, 7-ab_7 / l7benzazepine

10 ml of triethylamine were stirred into a solution of 5.5 g (+ ^ trans-i ^^^^ ajS ^ Ha-Octahydropyrido / V ^ ': 2,3 ^ ϊηαοΐ / ΐ, 7-ab_7 / \ 7benzazepine in 100 ml of chloroform. Then 5.76 g (0.04 mol) of 3-cyclohexene-i-carbonyl chloride in 10 ml of chloroform were added with stirring. The mixture was refluxed for 2 hours, then cooled and water was added. The organic Layer was separated, dried over KpCO-z and evaporated to dryness under reduced pressure. By triturating the residual oil in hexane became (+) - trans-3-Z "(3-Cyclohexen-1-yl) carbonyl7-1,2,3,4, 4a, 8,9,14a-octahydropyrido / 4 ', 3': 2,3_7indole / i, 7-ab7 / Ί7-benzazepine obtained from melting point 156.5-158.5 ° C.

This amide (7.4 g, 0.02 mol) was dissolved in 200 ml of benzene and added, with stirring and under nitrogen, to 34 ml of a reducing agent in 20 ml of benzene. The reducing agent consisted of a lOfcigen solution of sodium bis (2-methoxyethoxy) aluminum hydride in benzene. The resulting mixture was refluxed for 2 hours and then decomposed by slowly adding 100 ml of an aqueous 10% sodium hydroxide solution dropwise while cooling in an ice bath. The organic layer was washed neutral with water, over K ₂ CO,

40-9830 / 1106

dried, filtered and evaporated to dryness, leaving the desired compound as a solid which, after trituration in hexane had a melting point of 154.7 to 157.5 ° C.

The following further compounds of the formula I can, for example, by alkylation or by acylation / Reduction of the corresponding compounds in which R is a hydrogen atom to those in Examples 10 to 14 can be made in the manner described:

1) (+) - trans-1,2,3,4,4a, 8,9,14a-octahydro-3-ZT4-methylbicycloZ2.2.27oct-2-en-1 -yl) methyl_7pyrido / 4 ', 3': 2,37-indole / i, 7-ab / Z ~ i7benzazepine

2) (+) - trans-3- / T3-cyclohexen-1-yl) methyl / -1,2,3,4,4a, 8,9, 14a-octahydropyrido / 4 ', 3': 2,3_7indole / 1,7-ab7 / i7benzazepine

3) (+) -trans-1,2,3,4,4a, 8,9,14a-octahydro-3- / ~ (2,3-dimethylcycloprop-2-en-1-yl) inethyl7pyridO / 4 ^l , 3 ': 2,37 indole / T, 7-ab7 / i7benzazepine

4) (+) - trans-1,2,3,4,4a, 8,9,14a-octahydro-3- (3-methyl-2-butenyl) pyrido / 4 ', 3 ¹ : 2,37 indole / i , 7-ab7 / i7benzazepine

5) (+) -trans-3 - (trans-2-butenyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3': 2,37indole / 1,7- ab7 / i7 ^ enzazepine

6) (+) - trans-3- (cis-2-butenyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ¹ , 3 ': 2,37 indole / 1 ^ -

7) (+) - trans -3-cinnamyl-1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ·, 3 ': 2,37 indole / "i, 7-ab7 / ^: 17 ^ enzazepine

8) (+) - trans-3- (2-bromocinnamyl) -1,2,3,4,4a, 8,9,14a ~ octahydropyrido / 4- ·, 3 ': 2, 37indole / i, 7-ab7 / i7 ^ enzazepine

9) (+) - trans -3- (3-chlorocinnamyl) -1,2,3,4,4a, 8,9,14a-octahydropyrido / 4- ¹ , 3 ¹ : 2,3 ^ ϊηαο1 / Ί, 7 -ab7 / \ 7l) enzazepine

10) (+) - trans-3- (4-methoxycinnamyl) -1,2,3,4,4a, 8,9,14aoctahydropyrido / 4 ¹ , 3 ': 2,37indole / i, 7-ab7Z ^ 7 " benzazepine

409830/1106

11) (+) - trans-3- (3-butenyl) -1,2,3,4,4a, 8,9,14a-octahydro-pyrido / 4 ', 3 ^f : 2,57indole / i, 7- ab_7 / "i7t> enzazepine j

12) (+) - trans -3- (2-broraallyl) -1 _f 2,3,4,4a, 8,9, Ha-oc1: ahydropyrido / 4 ¹ , 3 ': 2,3 / indole / * 1 , 7-ab7 / i7t> enzazepine

13) (i) -trans-3- (2-butynyl) -1,2,3,4,4a _f 8,9,14a-octahydropyrido / 4 ', 3': 2,37 indole / i, 7-ab7 / i7t> enzazepine

14) (+) - trans-3-EBicyclo / 2.2.i7hept-2-en-5-yl) methylI-1.2,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3 ': 2.37 indole / Ί, 7-ab7 / i7tenzazepine

15) (+) - trans-3-Zi [2,4-cyclopentadien-1-yl) methyl7-1,2,3,4-

4a, 8,9,14a-octahydropyrido / 4 ', 3': 2,37,1HdOl ^ T, 7-ab? / T7-benzezepin ~

16) (+) - trans-3 - ^ &, 4-Cycloheptadien-1-yl) methyl7-1,2,3,4-4a, 8,9,14a-octahydropyrido / 4 ^! , 3 ': 2.37 indole / i, 7-β1ι7 / Ί7-benzazepine

17) (+) - trans -3 - / "(3-Cyclopen-ten-1-yl) methyl 7-1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ¹ , 3 ': 2 , 3_7indole / i , T-abJflJ- ■ benzazepine

18) (+) - trans-3- / T (cis-1,6-I) imethyl-enäo-3-norcaren-7-yl) -

. methy 17-1,2,3,4,4a, 8,9,14a-octahydropyridoA ', 3 ¹ ί2,37-indole / Ί, 7-ab7 / \ 7 ^ ^e n ^z azepine

19) (+) - trans-1,2,3,4,4a, 8,9,14a-octahydro-3-phenacylpyrido / 4 ', 3 ¹ : 2,37iodol / i, 7-a "b7 /" i7benzazepine

20) (+) - trans-1,2,3,4,4a, 8,9,14a-octahydro-3- (3-phenyl-2-propynyl) pyrido / 4 ', 3': 2.5 / indole / i, 7-ab7 / i7benzazepine

Pharmacological testing

The compounds according to the invention are effective as analgesics and sedative tranquilizers. The analgesic Effect is through the Phenylquinone Writhing (PQW) -iDest and the effect as a sedating tranquilizer demonstrated by the results of screening tests on rodents. The methods used are described below.

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Primary screening tests on rodents

Decreased locomotor activity (LMA) ι

Results in mg / kg oral / mouse

The strength of this reaction is measured subjectively by observing how an animal behaves when it is removed from an observation cage and placed on a table. Untreated animals immediately begin active exploration of their surroundings. Animals given a dampening compound show a gradually diminishing response to a new environment. The degree of stimulus or encouragement that must be given by the observer in order to achieve active motion is rated on an arbitrary scale. This scale ranges from a rating of -1, where only a light touch of the animal's body is required, to -10, where the animal does not respond or only responds minimally to the exertion of a painful stimulus (pressure on the base of the tail). The ED ₅₀ is the oral dose that produces an apparent reduction in locomotor activity (with a score of at least -1}. Groups of 5 mice each receive decreasing oral doses at intervals of 0.5 log (300, 100, 30 .. .etc.), until no effects on the behavior can be determined. A decrease in locomotor activity is an indication of a general central depressant effect.

Ptosis (Pto.) Results in mg / kg oral / mouse The degree of drooping of the upper eyelid serves as a measure of the central damping effect. An animal is removed from its observation cage and held outside the cage for 30 seconds. After this time has elapsed, the degree of drooping of the upper eyelid is assessed on an arbitrary scale. Passive ptosis, that is, drooping of the eyelid that is temporarily reversible by manipulation, is generally indicative of the sedative effects of a psychotropic compound.

409830/1 106

(Active ptosis, i.e. drooping of the eyelid that remains unchanged when manipulated, generally indicates an adrenergic blocking effect. This is a relatively seldom observed phenomenon ») In the case of the compounds according to the invention, their ED ™ is indicated is, only passive ptosis was observed "

Catalepsy (Cat.) Results in mg / kg oral / mouse

An animal's ability to maintain an abnormal stance serves as another indicator of a cushioning one Effect on the central nervous system. The test animal is removed from its observation cage and placed in a Positioned with his hind legs on the table and his front legs on the side of the observation cage are located. If an animal maintains this position for at least 10 seconds, it is believed that it shows cataleptic's behavior.

The analgesic effect of the compounds according to the invention is demonstrated in a simple manner by that described below Phenylquinone curvature pain test determined.

Phenylquinone Writhing (P.Q.W.) Results in mg / kg oral / mouse

Groups of at least 10 mice each receive phenyl-pbenzoquinone at a dose of 2.5 mg / kg intraperitoneally 30 minutes after oral administration of graduated doses of the test substance. Each compound is used in two or more dosages. For the purposes of the assessment, a "curvature of pain" is defined as stretching, inward turning of a hind leg or contraction of the abdomen. The total number of writhes in pain is determined for each of the treated animals and the comparison animals used at the same time over a period of 30 minutes. An EDc _Q > calculated based on the percentage of animals at each dose that had $ 50 or less of the average number of writhes in pain

409830/1106

the comparison animals showed is for each compound
that was subjected to this screening test. The PQW test is used extensively as an indication of the potential analgesic effect in humans, especially for non-narcotic substances.

The results obtained with some compounds according to the invention are given in the table below, in which also the results for codeine and chlorpromazine, used as standard substances for comparison are given.

link

CH

1, R = -CH ₂ -C = 1, R = -CH ₂ -CH = C-CH 1, R = -CH ₂ -CC

If

IP - PU, Π - —Ott-

I, R »H-

I, R

1, R

CH ₃ -

OH ₂ -

C_H_-

L.M.A. Cat. Ptn. 50 P.Q.W > 300 > 3OO > 300 > 300 86 36 112 36 > 300 2 2 15th > 300 2 7th 11 •
11 > 300 1 56 178 80 > 300 1 6 * 6 * 18 * > 300 1.9 2 » 2 * 6 * > 300 2.3 2 * 6 * 6 * > 300 0.4

409830/1106

L.M.A. Cat. Pto. 2A02 391 link l \ 6th 5 LD ₅₀ P.Q.W. I, R ^ (CH ₃ ) ₂ CHCH ₂ - 2 19th 13th > 300 1.75 I, R »^^ - CH ₂ - 16 5 20th > 300 28 I, R - £)> - CH ₂ - 6th 6th 6th > 3oo I, R «Q-CH ₂ - 11 15th 18th > 3oo 2.0 I, R - {_) " ^CH 2" 18th 28 8th > 300 13th I, R- ^ -CH ₂ CH ₂ - 5 6th 6th > 300 1.7 Chlorpromazine (HCl) - - - - - Codeine phosphate • - 19th ♦ appreciated

The free amines of the formula I and some of their pharmaceutically acceptable inorganic or organic Acid addition salts are essentially insoluble in water. As central damping substances, they are used on best administered orally in a dose of about 0.1 to 10 mg / kg body weight of the animal or warm-blooded animal. Some addition salts of the compounds of formula I are more water-soluble and can be subcutaneously or intramuscular injection. The dosage used in such cases is generally in the range of about 0.02 to 5 mg / kg body weight.

As analgesics, the compounds according to the invention are used orally in a dose of about 0.1 to 10 mg / kg or parenterally at a dose of about 0.05 * to 5 mg / kg body weight administered.

The compounds according to the invention can be used in pharmaceutical preparations, the one compound of formula I together with a pharmaceutically acceptable carrier The carrier can be solid or liquid and the preparations can be in the form of Tablets, liquid-filled capsules, dry-filled ones

409830/1 1 06

Capsules, aqueous solutions, non-aqueous solutions, suppositories, syrups, suspensions and the like. the Preparations can contain suitable preservatives, colorings and flavorings. As examples of Carriers that can be used for the manufacture of the products according to the invention may be mentioned: Gelatin capsules, sugars such as lactose and sucrose, starch, dextrans and cellulose compounds such as methyl cellulose and cellulose acetophthalate, gelatin, talc, stearic acid salts, vegetable oils, e.g. peanut oil, sesame oil, Olive oil, corn oil and theobroma oil, liquid petrolatum, polyethylene glycol, glycerine, sorbitol, propylene glycol, Ethanol, agar, water and isotonic saline solution.

Customary methods are used to produce the preparations according to the invention for pharmaceutical purposes and normal precautions taken. The preparations intended for parenteral administration must be sterile and this can be achieved using either sterile ingredients and the Manufacturing is done under aseptic conditions, or by adding the final preparation after a the usual methods, e.g. by treatment in an autoclave under suitable temperature and pressure conditions, is sterilized. The usual precautionary measures must be taken to avoid an incompatible state between the active components and the diluting preservative or flavoring agent or among those used in manufacture the conditions applied to the preparations are met.

The pharmaceutical preparations according to the invention can Oral, rectal or parenteral administration to warm-blooded animals. This can be for liquid or solid preparations by swallowing, by suppositories, or by intravenous, intramuscular, intraperitoneal or subcutaneous routes Injection of the liquid preparations are done.

409830/1106

24U2391

The compounds according to the invention are administered to warm-blooded animals to produce the desired pharmacological response to create. The dosage forms come in different strengths depending on the effectiveness of the compound and produced the desired effect. For example, it is possible to determine the likely dose for the Estimating humans for analgesia by the analgesic dose in the animal for the compound according to the invention is compared with the dose of a standard drug in the same animal. For example, according to Example 13, the compound produced the following analgesic effect in comparison to codeine phosphate:

₅₀ as an anesthetic

Usual
Dose at
people

Concentration of the dosage form

Codeine phosphate 19 mg / kg

15-300 mg /
Day

15-60 mg

connection of
Example 13

1 mg / kg

1-15 mg / day 1-15 mg

Since the compound prepared according to Example 13 is about 20 stronger than codeine phosphate, its dose is determined for humans with 1 to 15 mg / day (1/20 of the codein dose). The dosage forms of the compound contain usually 1 to 15 mg of the active ingredient, however lower or higher concentrations can be used in

of

Depending on the age and condition / patient to be treated, the severity of the pain and the required Frequency of treatment may be necessary.

In the same way, the concentration of the dosage forms for human use by comparing the effects of a standard drug such as chlorpromazine and the compounds according to the invention can be determined in the same animal.

409830/1 106

-38- 24Ü2391

LMA Cat- Ptosis Usual Concentration

lepsy dose at tion of the

People, dosage form mg / day

Chlorpromazine 5 6th 6th 10-1000 10-200 mg connection of
Example 12 CVJ 15th 4th 10-1000 10-200 mg connection of
Example 13 7th 11 11 10-1000 10-200 mg

Since the above-mentioned compounds according to the invention have a similar activity as chlorpromazine Animal studies, dosages similar to those recommended for chlorpromazine will be used for humans, estimated.

Typical formulations of the above type used for the administration of these compounds are mentioned in the following examples.

Example A Ingredients ' mg / tablet

3- (allyl) -1,2,3,4,4a, 8,9, Ha-octahydro-

pyrido / 4 ^! , 3 ': 2, 3jindol / i, 7-abJf \ Jhe nz-

azepine 15 mg

Lactose, USP 185 mg

The above ingredients are passed through a suitable sieve, mixed for 20 minutes and with a suitable tablet press with 8.73 mm punch and - die pressed directly into tablets of 200 mg.

Example B. Components , 2,3,4,4aj8,9,14a-
, 3jindol / 1,7-ab_7 / i7- mg / tablet mg 3- (3-chloro-2-butenyl) -1.
octahyaropyrido / 4 ', 3': 2, mg benzazepine hydrochloride 50 mg Lactose, USP 215 mg Methyl cellulose, USP 15th mg Talc, USP 6th Strength, USP 10

409830/1 106

Magnesium stearate, USP 4 mg

Dye (if desired) as needed

The lactose and the active ingredient are wet granulated with a methyl cellulose solution in a mixer, until a satisfactory mass has formed. The mass is dried and passed through a suitable sieve. The remaining ingredients are passed through a sieve with a mesh size of 0.177 mm and mixed with the dried mixed granulated material. The mixture is then pressed with a suitable tablet press with a 9.53 mm punch and die pressed into tablets of 300 mg.

Example C. Components

3-acetonyl-1,2,3,4,4a, 8,9,14a-octahydropyrido / 4 ', 3': 2,3 / indole / i, 7-ab7 / i7benzazepine

Lactose, USP
Magnesium Stearate, USP Colloidal Silica, NF

All ingredients are mixed and passed through a sieve with a mesh size of 0.46 mm. The mixture will Filled into two-part hard gelatine capsules Kr.3 on a suitable machine with a net weight of 128 g.

mg / capsule mg 25th mg 100 mg 1 mg 2

Λ09830 / 1 106

Claims (21)

Claims Compounds of the formula (n) HX in the η = O or 1, i _; X = an anion of a pharmaceutically acceptable acid and R = hydrogen, 3-chloro-2-butenyl, 2-bromoallyl, benzyl, a benzyl radical ring-substituted with methyl, methoxy or chlorine, phenylethyl, 3-phenylpropyl, a 3-phenylpropyl radical ring-substituted with chlorine, bromine or methoxy, furfuryl, 2- Thenyl, acetonyl, phenacyl, Cj-Cpj-ALcyl., C, -Cf - alkenyl, C, -C ₁ - alkynyl, cinnamyl, a cinnamyl radical which is ring-substituted with chlorine, bromine or methoxy, 3-phenyl-2-propynyl, cyclopropyl, C.-Cg cycloalkylmethyl, (methylcyclopropyl) methyl, (cis-2,3-dimethylcyclopropyl) methyl, Cg-Cg-cycloalkenylmethyl, Cg-C _Q -Cycloalkadienylmethyl, (2,3-Dimethylcycloprop-2-en-1 -yl) methyl, exo-7-norcarylmethyl, (cis-1,6-dimethyl-endo-3-norcaren-7-yl) methyl, (4-methylbicyclo _i /2.2c27oct-1-yl) methyl, (4- Methylbicyclo-Z * 2,2.27oct-2-en-1-yl) methyl, (bicyclo / 2.2.27hept-2-yl) methyl, (bicyclo / 2.2.27hept-2-en-5-yl) methyl, 1 -Adamantylmethyl or 2-Adamantylmethyl 409830/1106 and the hydrogen atoms in the 4a and Ha positions are in trans-configuration to each other » 2) The free base and hydrochloride of the compounds according to claim 1 with the formula mentioned there, in which R is a hydrogen atom. 3) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is a methyl radical. 4) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is cyclopropylmethyl. 5) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is an ethyl radical. i; 6) The free base and hydrochloride of the compounds according to Claimi with the formula mentioned there, in which R is isobutyl. 7) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is benzyl. 8) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is exo-7-norcarylmethyl. 9) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is 1-adamantylmethyl. 10) The free base and hydrochloride of the compounds according to claim 1 with the formula mentioned therein, in which R is a 2-adamantylmethyl radical. '409830/1106 11) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is 3-chloro-2-butenyl. 12) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is 2-propynyl. 13) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is an acetonyl radical » 14) The free base and the hydrochloride of the compounds according to claim 1 with the formula mentioned there in which R is an allyl radical. 15) Medicinal preparations, consisting essentially of a pharmaceutically acceptable carrier and at least one compound according to Claims 1 to 14. 16) Process for the preparation of compounds according to claim 1 having the formula (n) HX Yes in which the hydrogen atoms in the 4a and 14a positions are in trans configuration to each other, η = 0 or 1, 409830/1 106 X = an anion of a pharmaceutically acceptable one Acid and. : R ^a = benzyl, a benzyl radical which is ring-substituted with methyl, methoxy or chlorine, phenylethyl, 3-phenylpropyl, a 3-phenylpropyl radical which is ring-substituted with chlorine, bromine or methoxy, furfuryl, 2-thenyl, Cj-Cc-alkyl, cyclopropyl, C ^ - Cg-Cycloalkylmethyl, (methylcyclopropyl) methyl, exo-7-norcarylmethyl, (4-methyltiicyclo / f2.2.27oct-1 yl) methyl, (bicyclo / ^. 2.27hept-1-yl) methyl, 1-adamantylmethyl or 2 -Adamantylmethyl, characterized in that compounds of the formula 2 a in which R has the same meaning as R or a methoxymethyl radical or a group of the formula -CR, in which R 'is a phenyl radical, chlorophenyl, methylphenyl, methoxyphenyl, benzyl, phenylethyl, a phenylethyl radical which is ring-substituted with chlorine, bromine or methoxy, 2-furyl, 2-thienyl, hydrogen, O ₁ -C ^ -AIkYl, C. ₂ -C ₄ -alkenyl, styryl, a styryl radical which is ring-substituted with chlorine, bromine or methoxy, C ₅ -C ₇ cycloalkyl, methylcyclopropyl, C 1 -C 4 cycloalkenyl, C ₅ -C ₇ cycloalkadienyl, 2,3-dimethylcycloprop -2-en-1-yl, exo-7-norcaryl, l-methylbicyclo / ^^^ oct-iyl, bicyclo / 2.2.i7hept-2-yi, 4-metbyll3icycloZ2.2.27- 409830/1106 oct-2-en-i-yl, bicyclo / 2 ₀ 2.2 / hept-2-en-5-yl, 1-ada · - mantyl or 2-adamantyl, reduced with a borohydride / tetrahydrofuran-iComplex and the free base optionally converted into a salt by reaction with a pharmaceutically acceptable acid. 17) Process for the preparation of compounds according to claim 1 with the formula mentioned there, in which R is a Is hydrogen atom, characterized in that one Compounds according to claim 1 having the formula (n) HX in which the hydrogen atoms in the 4a and 14a position are in the trans configuration to one another and R is methyl, ethyl, benzyl, a benzyl radical ring-substituted with chlorine, methyl or methoxy, or cyclopropylmethyl, with a compound of the formula ClCOOR ³ , in which R ⁵ C ₁ -C ^ alkyl, vinyl, benzyl, p-methylbenzyl, p-methoxybenzyl or phenyl, to a compound of the formula 409830/1 1 06 converts and this compound of hydrolysis or if R is benzyl or substituted benzyl, subjected to hydrolysis or hydrogenolysis. 18) Process for the preparation of compounds according to claim 1 with the formula '' (n) HX in which R has the abovementioned meaning, η is O or 1, X is the anion of a pharmaceutically acceptable acid and the hydrogen atoms in the 4a and 14a positions are in the trans configuration to one another, characterized in that compounds according to claim 1, in which R is a hydrogen atom, alkylated in the presence of an acid acceptor with an alkylating agent of the formula R ⁰ Z, in which 409830/1106 R = 3-chloro-2-butenyl, 2-bromoallyl, benzyl, a rait Methyl, methoxy or chlorine ring-substituted benzyl radical, phenylethyl, 3-phenylpropyl, one with chlorine, Bromine or methoxy ring-substituted 3-phenylpropyl radical, Furfuryl, 2-thenyl, acetonyl, phenacyl, C ^ -Cf - alkyl, C 1 -C 4 alkenyl, C 1 -C (-alkynyl, cinnamyl, a Cinnamyl radical substituted with chlorine, bromine or methoxy, 3-pbenyl-2-propynyl, C.-Cg-cycloalkylmethyl, (Methylcyclopropyl) methyl, Cg-Cg-cycloalkenylmethyl, Cg-Cg-Cycloalkadienylmethyl, (2,3-Dimethylcycloprop-2-en-1-yl) methyl, exo-7-norcarylmethyl, (cis-1,6-dimethyl-endo-3-norcaren-7-yl) methyl, (4-methylbicycloZ2.2.27oct-1-yl) methyl, (4-methylbicyclo / * 2.2 ο 2 / oct-2-en-1 -yl) methyl, (bicyclo / 2.2.2 / hept-2-yl) methyl, (bicyclo / 2.2.27hept-2-en-5-yl) methyl, 1-adamantylmethyl or 2-adamantylmethyl, Z = -Cl, -Br, -I or -OS (O) ₂ R ⁸ , · R ⁸ = CH ₅ , phenyl or p-tolyl and R ⁰ Z can also ^{stand for R 9} OS (O) ₂ OR ⁹ , in which R ^{9 is} a Cj-C ^ -alkyl radical, and the free base, optionally by reaction with a pharmaceutically acceptable acid, into a salt converts. 19) Process for the preparation of compounds according to claim 1 having the formula 409830/1106 24Ü2391 in which the hydrogen atoms in the 4a and Ha positions are in trans configuration to each other, j η = 0 or 1, j X = the anion of a pharmaceutically acceptable acid and R ^d = 3-chloro-2-butenyl, 2-bromoallyl, benzyl, a benzyl radical which is ring-substituted with methyl, methoxy or chlorine, phenylethyl, 3-phenylpropyl, a 3-phenylpropyl radical which is ring-substituted with chlorine, bromine or methoxy, furfuryl, 2-thenyl , C ₁ -C ₅ -alkyl, C ₅ -C ₅ -AliCenyl, C ^ -C ^ -alkynyl, C ^ -Cg-cycloalkylmethyl, (methylcyclopropyl) methyl, Cg-Cg-cycloalkenylmethyl, Cg-Cg-cycloalkadienylmethyl, ( 2,3-Dimethylcycloprop-2-en-1-yl) methyl, exo-7-norcarylmethyl, (cis-1,6-dimethyl-endo-3-norcaren-7-yl) methyl, (4-methylbicyclo / 2.2. 27oct-2-en-1-yl) methyl, (bicyclo / 2.2.27hept-2-yl) methyl, (bicyclo / 2.2.27hept-2-enyl-5-yl) methyl, 1-adamantylmethyl or 2-adamantylmethyl, characterized in that the compound according to claim 1, in which R is a hydrogen atom, with an acylating agent of the formula " . QCR ⁴ acylated, wherein R = 2-chloro-1-propenyl, 1-bromovinyl, phenyl, chlorophenyl, methylphenyl, metboxyphenyl, benzyl, phenylethyl, phenylethyl which is ring-substituted with chlorine, bromine or methoxy,. 2-furyl, 2-thienyl, hydrogen, C ^ C ^ -alkyl, C ₂ -C.-alkenyl, Crj-Cq-klkynyl, styryl, a styryl radical which is ring-substituted with chlorine, bromine or methoxy, phenylethinyl, C ₅ -C ₇ -Cycloalkyl, methylcyclopropyl, C ₅ -C ₇ cycloalkenyl, C ^ O ^ cycloalkadienyl, 2,3-dimethylcycloprop-2-en-1-yl, exo-7-norcaryl, cis-1, e-dimethyl-endo ^ -norcaren ^ -yl, 4-methylbicyclo / 2.2.2 / oct-1-yl, bicyclo / 2.2.27hept-2-yl, A098 3 0/1106 ^ - methylbicyclo / ^^^ / oct ^ -en-i-yl, bicyclo- / 2.2.27hept-2-en-5-yl, 1-adamantyl or 2-ada-. mantyl, ·! 0 0 I Q s -Cl, -Br, Cj-C.-Alkoxy, RCO-, RCO- or 0 R ⁰ OCO, i R "^ is different from R and is a C« -C, -alkyl radical, with the proviso that in cases in which R 5
Is hydrogen, R is methyl, and R = C.-C, -alkyl, with formation of an amide of the formula wherein R has the meaning given above, the Carbonyl group of the amide reduced with a metal hydride to a methylene radical and optionally the free base obtained by reaction with a pharmaceutically acceptable acid turns into a salt. i 20) Process for the preparation of compounds of the formula I in which R is (cis-2,3-dimethylcyclopropyl) methyl, characterized in that compounds of the formula I in which R (2,3-dimethylcycloprop-2-en-1-yl) methyl is catalytically hydrogenated. : 409830/1 1 06 21) compounds of formula in IT for Cj-C ^ -alkyl, vinyl, benzyl, p-methyl- "benzyl, p-methoxybenzyl or phenyl and the hydrogen atoms in the 4a and 14a positions in the trans configuration to stand by each other. 409830/1106